QbD for pediatric oral lyophilisates development: risk assessment followed by screening and optimization

Objective: This study proposed the development of oral lyophilisates with respect to pediatric medicine development guidelines, by applying risk management strategies and DoE as an integrated QbD approach.

Methods: Product critical quality attributes were overviewed by generating Ishikawa diagrams for risk assessment purposes, considering process, formulation and methodology related parameters. Failure Mode Effect Analysis was applied to highlight critical formulation and process parameters with an increased probability of occurrence and with a high impact on the product performance. To investigate the effect of qualitative and quantitative formulation variables D-optimal designs were used for screening and optimization purposes.

Results: Process parameters related to suspension preparation and lyophilization were classified as significant factors, and were controlled by implementing risk mitigation strategies. Both quantitative and qualitative formulation variables introduced in the experimental design influenced the product’s disintegration time, mechanical resistance and dissolution properties selected as CQAs. The optimum formulation selected through Design Space presented ultra-fast disintegration time (5?seconds), a good dissolution rate (above 90%) combined with a high mechanical resistance (above 600?g load).

Conclusions: Combining FMEA and DoE allowed the science based development of a product with respect to the defined quality target profile by providing better insights on the relevant parameters throughout development process. The utility of risk management tools in pharmaceutical development was demonstrated.     

Development of a PC-based data acquisition system for performancemonitoring on an 81 megawatt steam cycle electric power generating unit

A computer-based performance monitoring system has been successfully developed and implemented on an 81 MW steam cycle generating unit. The instrument, data acquisition, computer, and software requirements for the system are discussed. This PC-based system was designed in such a manner that it is transparent to the unit's existing control scheme. Data from this system permits the setting of operating limits to avoid ongoing problems of turbine blade damage     

A study of polyphase watthour meter accuracy comparing single phaseseries to polyphase calibration

This paper examines the accuracy of polyphase watthour meters derived from two methods of calibration. The standard single phase series method is compared to the three phase method of calibrating polyphase transformer rated and self-contained induction type watthour meters. A total of seventy two meters from four different manufactures are tested. Sixty of these meters are tested at full load, full load with 0.5 lagging power factor and light load for each of the calibration methods. Twelve meters are further tested over a greater range of loading conditions. Also, the effect of rotating the phase of the input conductors on the meter's accuracy is examined     

Can Mean‐Curvature Flow be Modified to be Non‐singular?

This work considers the question of whether mean‐curvature flow can be modified to avoid the formation of singularities. We analyze the finite‐elements discretization and demonstrate why the original flow can result in numerical instability due to division by zero. We propose a variation on the flow that removes the numerical instability in the discretization and show that this modification results in a simpler expression for both the discretized and continuous formulations. We discuss the properties of the modified flow and present empirical evidence that not only does it define a stable surface evolution for genus‐zero surfaces, but that the evolution converges to a conformal parameterization of the surface onto the sphere.     

Connecting Polygonizations via Stretches and Twangs

We show that the space of polygonizations of a fixed planar point set S of n points is connected by O(n ²) “moves” between simple polygons. Each move is composed of a sequence of atomic moves called “stretches” and “twangs,” which walk between weakly simple “polygonal wraps” of S. These moves show promise to serve as a basis for generating random polygons.     

Nanoparticles with entrapped α-tocopherol: synthesis, characterization, and controlled release

An emulsion evaporation method was used to synthesize spherical poly(DL-lactide-co-glycolide) (PLGA) nanoparticles with entrapped α-tocopherol. Two different surfactants were used: sodium dodecyl sulfate (SDS) and poly(vinyl alcohol) (PVA). For SDS nanoparticles, the size of the nanoparticles decreased significantly with the entrapment of α-tocopherol in the PLGA matrix, while the size of PVA nanoparticles remained unchanged. The polydispersity index after synthesis was under 0.100 for PVA nanoparticles and around 0.150 for SDS nanoparticles. The zeta potential was negative for all PVA nanoparticles. The entrapment efficiency of α-tocopherol in the polymeric matrix was approximately 89% and 95% for nanoparticles with 8% and 16% α-tocopherol theoretical loading, respectively. The residual PVA associated with the nanoparticles after purification was approximately 6% ( w/w relative to the nanoparticles). The release profile showed an initial burst followed by a slower release of the α-tocopherol entrapped inside the PLGA matrix. The release for nanoparticles with 8% α-tocopherol theoretical loading (86% released in the first hour) was faster than the release for the nanoparticles with 16% α-tocopherol theoretical loading (34% released in the first hour).     

Biosynthesis and isomerization of 11-hydroperoxylinoleates by manganese- and iron-dependent lipoxygenases

Manganese lipoxygenase (Mn-LO) oxygenates linoleic acid (LA) to a mixture of the hydroperoxides—11(S)-hydroperoxy-9Z,12Z-octadecadienoic acid [11(S)-HPODE] and 13(R)-hydroperoxy-9Z,11E-octadecadienoic acid [13(R)-HPODE]- and also catalyzes the conversion of 11(S)-HPODE to 13(R)-HPODE via oxygen-centered (LOO•) and carbon-centered (L•) radicals [Hamberg, M., Su, C., and Oliw, E. (1998) Manganese Lipoxygenase. Discovery of a Bis-allylic Hydroperoxide as Product and Intermediate in a Lipoxygenase Reaction, J. Biol. Chem. 273, 13080–13088]. The aims of the present work were to investigate whether 11-HPODE can also be produced by iron-dependent lipoxygenases and to determine the enzymatic transformations of stereoisomers of 11-HPODE by lipoxygenases. Rice leaf pathogen-inducible lipoxygenase, but not soybean lipoxygenase-1 (sLO-1), generated a low level of 11-HPODE (0.4%) besides its main hydroperoxide, 13(S)-HPODE, on incubation with LA. Steric analysis revealed that 11-HPODE was enriched with respect to the R enantiomer [74% 11(R)]. In agreement with previous results, 11(S)-HPODE incubated with Mn-LO provided 13(R)-HPODE, and the same conversion also took place with the methyl ester of 11(S)-HPODE. 11(R,S)-HPODE was metabolized biphasically in the presence of Mn-LO, i.e., by a rapid phase during which the 11(S)-enantiomer was converted into 13(R)-HPODE and a slow phase during which the 11(R)-enantiomer was converted into 9(R)-HPODE. sLO-1 catalyzed a slow conversion of 11(S)-HPODE into a mixture of 13(R)-HPODE (75%), 9(S)-HPODE (10%), and 13(S)-HPODE (10%), whereas 11(R,S)-HPODE produced a mixture of nearly racemic 13-HPODE (≈70%) and 9-HPODE (≈30%). The results showed that 11-HPODE can also be produced by an iron-dependent LO and suggested that the previously established mechanism of isomerization of 11(S)-HPODE involving suprafacial migration of O₂ is valid also for the isomerizations of 11(R)-HPODE by Mn-LO and of 11(S)-HPODE by sLO-1.     

Nonsinusoidal electrical measurement accuracy in adjustable-speedmotors and drives

Accurate measurements of voltage, current and power under nonsinusoidal conditions are essential for determining the efficiency of a drive system and performing separation of losses between an adjustable-speed drive (ASD) and an electric motor. That information is invaluable for equipment designers, manufacturers and users. Three modern power meters and analyzers were tested to determine their accuracy with various nonsinusoidal waveforms applied. The meters were subjected to waveforms that are characteristic to the three most common fractional and integral horsepower ASD technologies, namely, pulsewidth modulation induction, brushless DC and switched-reluctance drives. The tests were performed under field conditions and in a computer-controlled laboratory environment. The obtained results show that some meters are able to measure accurately electric power at the input to ASDs. However, the output power of ASDs for brushless DC and switched-reluctance technology was not measured with acceptable accuracy by any of the tested meters. Possible reasons of meters inaccuracies and suggestions for performance improvement are presented. Conclusions on the present state of ASD electric power measurements and recommendations for further research are given